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Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.

Méhats C, Franco-Montoya ML, Boucherat O, Lopez E, Schmitz T, Zana E, Evain-Brion D, Bourbon J, Delacourt C, Jarreau PH - PLoS ONE (2008)

Bottom Line: The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche médicale U767, Paris, France.

ABSTRACT

Background: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.

Methodology/findings: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.

Conclusions: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

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Related in: MedlinePlus

Growth of rat pups exposed to hyperoxia and treated or not with rolipram.Growth curves of rat pups exposed to normoxia or hyperoxia (circles and triangles, respectively), and either treated with rolipram (open symbols) or receiving the diluent alone (littermate controls, closed symbols). Values are mean±sem. Sixteen to 21 rat pups were included on day 0. * Significantly different from air-diluent group; † significantly different from air-rolipram group. Note that except for day 1 and day 2, all values of rolipram-treated pups were significantly lower than those of oxygen-diluent-treated pups.
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pone-0003445-g006: Growth of rat pups exposed to hyperoxia and treated or not with rolipram.Growth curves of rat pups exposed to normoxia or hyperoxia (circles and triangles, respectively), and either treated with rolipram (open symbols) or receiving the diluent alone (littermate controls, closed symbols). Values are mean±sem. Sixteen to 21 rat pups were included on day 0. * Significantly different from air-diluent group; † significantly different from air-rolipram group. Note that except for day 1 and day 2, all values of rolipram-treated pups were significantly lower than those of oxygen-diluent-treated pups.

Mentions: Gain in body weight was different among all groups (p<0.001 by ANOVA). Hyperoxia impaired weight gain of pups all over the 10 first days of life (Figure 6). Rolipram administration decreased weight gain either under hyperoxia or normoxia in the same proportions. The decrease induced by rolipram was larger than that consecutive to hyperoxia exposure, the day-10 body weight being decreased about one third.


Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.

Méhats C, Franco-Montoya ML, Boucherat O, Lopez E, Schmitz T, Zana E, Evain-Brion D, Bourbon J, Delacourt C, Jarreau PH - PLoS ONE (2008)

Growth of rat pups exposed to hyperoxia and treated or not with rolipram.Growth curves of rat pups exposed to normoxia or hyperoxia (circles and triangles, respectively), and either treated with rolipram (open symbols) or receiving the diluent alone (littermate controls, closed symbols). Values are mean±sem. Sixteen to 21 rat pups were included on day 0. * Significantly different from air-diluent group; † significantly different from air-rolipram group. Note that except for day 1 and day 2, all values of rolipram-treated pups were significantly lower than those of oxygen-diluent-treated pups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2563688&req=5

pone-0003445-g006: Growth of rat pups exposed to hyperoxia and treated or not with rolipram.Growth curves of rat pups exposed to normoxia or hyperoxia (circles and triangles, respectively), and either treated with rolipram (open symbols) or receiving the diluent alone (littermate controls, closed symbols). Values are mean±sem. Sixteen to 21 rat pups were included on day 0. * Significantly different from air-diluent group; † significantly different from air-rolipram group. Note that except for day 1 and day 2, all values of rolipram-treated pups were significantly lower than those of oxygen-diluent-treated pups.
Mentions: Gain in body weight was different among all groups (p<0.001 by ANOVA). Hyperoxia impaired weight gain of pups all over the 10 first days of life (Figure 6). Rolipram administration decreased weight gain either under hyperoxia or normoxia in the same proportions. The decrease induced by rolipram was larger than that consecutive to hyperoxia exposure, the day-10 body weight being decreased about one third.

Bottom Line: The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche médicale U767, Paris, France.

ABSTRACT

Background: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.

Methodology/findings: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.

Conclusions: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

Show MeSH
Related in: MedlinePlus